bims-netuvo Biomed News
on Nerves in tumours of visceral organs
Issue of 2022–05–15
nine papers selected by
Maksym V. Kopanitsa, The Francis Crick Institute
  1. Exploring the Role of Metabolites in Cancer and the Associated Nerve Crosstalk.
  2. Regulation of Carcinogenesis by Sensory Neurons and Neuromediators.
  3. RET-Dependent Axonal Sprouting from Spinal Afferent Neurons in a Pancreatic Cancer Model.
  4. Perineural invasion is a prognostic factor in stage II colorectal cancer but not a treatment indicator for traditional chemotherapy: a retrospective cohort study.
  5. Perineural Invasion in Pancreatic Ductal Adenocarcinoma (PDAC): A Saboteur of Curative Intended Therapies?
  6. Chronic Cancer Pain: Opioids within Tumor Microenvironment Affect Neuroinflammation, Tumor and Pain Evolution.
  7. The µ-Opioid Receptor in Cancer and Its Role in Perineural Invasion: A Short Review and New Evidence.
  8. Mapping and specific viral targeting of peripheral pancreatic innervation.
  9. SPARC: Visualization of genetically-labeled vagal and spinal afferent subsets innervating the mouse lung.
  1. Nutrients. 2022 Apr 21. pii: 1722. [Epub ahead of print]14(9):
    Exploring the Role of Metabolites in Cancer and the Associated Nerve Crosstalk.
    Inah Gu, Emory Gregory, Casey Atwood, Sun-Ok Lee, Young Hye Song.
      Since Otto Warburg's first report on the increased uptake of glucose and lactate release by cancer cells, dysregulated metabolism has been acknowledged as a hallmark of cancer that promotes proliferation and metastasis. Over the last century, studies have shown that cancer metabolism is complex, and by-products of glucose and glutamine catabolism induce a cascade of both pro- and antitumorigenic processes. Some vitamins, which have traditionally been praised for preventing and inhibiting the proliferation of cancer cells, have also been proven to cause cancer progression in a dose-dependent manner. Importantly, recent findings have shown that the nervous system is a key player in tumor growth and metastasis via perineural invasion and tumor innervation. However, the link between cancer-nerve crosstalk and tumor metabolism remains unclear. Here, we discuss the roles of relatively underappreciated metabolites in cancer-nerve crosstalk, including lactate, vitamins, and amino acids, and propose the investigation of nutrients in cancer-nerve crosstalk based on their tumorigenicity and neuroregulatory capabilities. Continued research into the metabolic regulation of cancer-nerve crosstalk will provide a more comprehensive understanding of tumor mechanisms and may lead to the identification of potential targets for future cancer therapies.
    Keywords:  amino acid metabolism; cancer; cancer–nerve crosstalk; lactate; metabolites; perineural invasion; tumor innervation; vitamins
    DOI:  https://doi.org/10.3390/nu14091722
  2. Cancers (Basel). 2022 May 09. pii: 2333. [Epub ahead of print]14(9):
    Regulation of Carcinogenesis by Sensory Neurons and Neuromediators.
    Nuray Erin, Galina V Shurin, James H Baraldi, Michael R Shurin.
      Interactions between the immune system and the nervous system are crucial in maintaining homeostasis, and disturbances of these neuro-immune interactions may participate in carcinogenesis and metastasis. Nerve endings have been identified within solid tumors in humans and experimental animals. Although the involvement of the efferent sympathetic and parasympathetic innervation in carcinogenesis has been extensively investigated, the role of the afferent sensory neurons and the neuropeptides in tumor development, growth, and progression is recently appreciated. Similarly, current findings point to the significant role of Schwann cells as part of neuro-immune interactions. Hence, in this review, we mainly focus on local and systemic effects of sensory nerve activity as well as Schwann cells in carcinogenesis and metastasis. Specific denervation of vagal sensory nerve fibers, or vagotomy, in animal models, has been reported to markedly increase lung metastases of breast carcinoma as well as pancreatic and gastric tumor growth, with the formation of liver metastases demonstrating the protective role of vagal sensory fibers against cancer. Clinical studies have revealed that patients with gastric ulcers who have undergone a vagotomy have a greater risk of stomach, colorectal, biliary tract, and lung cancers. Protective effects of vagal activity have also been documented by epidemiological studies demonstrating that high vagal activity predicts longer survival rates in patients with colon, non-small cell lung, prostate, and breast cancers. However, several studies have reported that inhibition of sensory neuronal activity reduces the development of solid tumors, including prostate, gastric, pancreatic, head and neck, cervical, ovarian, and skin cancers. These contradictory findings are likely to be due to the post-nerve injury-induced activation of systemic sensory fibers, the level of aggressiveness of the tumor model used, and the local heterogeneity of sensory fibers. As the aggressiveness of the tumor model and the level of the inflammatory response increase, the protective role of sensory nerve fibers is apparent and might be mostly due to systemic alterations in the neuro-immune response. Hence, more insights into inductive and permissive mechanisms, such as systemic, cellular neuro-immunological mechanisms of carcinogenesis and metastasis formation, are needed to understand the role of sensory neurons in tumor growth and spread.
    Keywords:  metastasis; neuro-immunology; neuropeptides; tumor innervation
    DOI:  https://doi.org/10.3390/cancers14092333
  3. FASEB J. 2022 May;36 Suppl 1
    RET-Dependent Axonal Sprouting from Spinal Afferent Neurons in a Pancreatic Cancer Model.
    Samira Osman, Bryanna Thomson, Brandy Hyndman, Lois Mulligan, Alan E Lomax.
       OBJECTIVE: Activation of the RET receptor tyrosine kinase stimulates signaling pathways associated with cell proliferation, growth, differentiation, and survival. Changes in the expression of this receptor and its associated ligands have been linked to tumorigenesis in several tumor types, including pancreatic cancer. It has been established that tumor cells can migrate towards and invade cells of the nervous system, a process called perineural invasion that is associated with metastasis and reduced survival. Given that RET ligands play important roles in spinal afferent neuronal development and morphology, we hypothesized that the release of RET ligands by pancreatic cancer cells has a neurotrophic effect on spinal afferent neurons, drawing their axons towards the tumor and facilitating perineural invasion.
    METHODS: Thoraco-lumbar (T10-L2) dorsal root ganglion (DRG) neurons from male C57BL/6 mice were collected, dissociated, and cultured for 4 days in F12 media along with a 1:3 dilution of conditioned media from two pancreatic cancer cell lines (PanC1 and MiaPaCa2) or a cell-free media control (F12 + 1:3 DMEM). In a separate set of experiments, DRG neurons were exposed to the same conditioned media along with the RET inhibitor, Selpercatinib (5 µM, diluted in DMSO). For the RET inhibitor experiments two control groups were used, the 1st contained F12 media + 1:3 DMEM + DMSO (vehicle controls, VC), and the 2nd group of controls consisted of F12 media + 1:3 DMEM + Selpercatinib (VC + Selp). Neurons were stained with calcein-AM (1 µM) and visualized using a fluorescent microscope. Changes in DRG neuron morphology (neurite length and branching relative to distance from cell soma) were quantified using Sholl analysis.
    RESULTS: Sholl plots revealed significant changes in DRG neuron morphology following treatment with either PanC1 or MiaPaCa2 conditioned media compared to DRG neurons treated with the RET inhibitor, or the different control groups. Where DRG neurons incubated with PanC1 conditioned media demonstrated an approximate 3 to 4-fold increase in neurite length compared to VC and VC + Selp (229 ± 32.7 µm vs 74.7 ± 12.2 µm vs 50.2 ± 6.3 µm; respectively). These effects on neurite length were significantly diminished following treatment of the DRG neurons with PanC1 + Selp (116.6 ± 15.5 µm). Furthermore, treatment of DRG neurons with the PanC1 conditioned media led to a 2-fold increase in the maximum branching of neurites (10.4 ± 2.1 intersections; n=36) compared to VCs (5.75 ± 1.3 intersections; n=35). Again, these effects were significantly diminished following treatment of DRG neurons with PanC1 conditioned media + Selp (3.75 ± 0.6 intersections; n=40) (Kruskal-Wallis with Dunn's post-hoc multiple comparison test, p<0.001). Similar RET-dependent effects were observed for DRG neurons treated with conditioned media from the MiaPaCa2 cell line.
    CONCLUSION: These data suggest that pancreatic cell lines release RET ligands that may attract axons of spinal afferent neurons towards them, which may facilitate perineural invasion.
    DOI:  https://doi.org/10.1096/fasebj.2022.36.S1.R2712
  4. J Gastrointest Oncol. 2022 Apr;13(2): 710-721
    Perineural invasion is a prognostic factor in stage II colorectal cancer but not a treatment indicator for traditional chemotherapy: a retrospective cohort study.
    Juan Li, Shiwen Mei, Sichen Zhou, Fuqiang Zhao, Qian Liu.
       Background: Perineural invasion (PNI) is considered a risk factor of survival but does not yet inform treatment decisions, and has not been studied separately in stage II colorectal cancer (CRC) patients whose postoperative traditional chemotherapy is controversial. This cohort study aimed to assess the association of PNI with basic clinicopathological features and patient outcomes after curative resection and the effects of PNI on responses to adjuvant chemotherapy in stage II CRC.
    Methods: The clinical data of 371 stage II CRC patients who underwent curative-intent surgery at the National Cancer Center/Cancer Hospital in 2014 were retrospectively reviewed. The adjuvant chemotherapy data were acquired from follow-up information. PNI status was examined, and the overall survival (OS) and disease-free survival (DFS) rates were analyzed.
    Results: PNI was detected in 82 of the 371 patients (22.1%) and was closely correlated with preoperative serum carcinoembryonic antigen (CEA) levels (P=0.030), gross tumor type (P=0.010), tumor differentiation (P=0.010), p stage (P<0.001), and extramural vascular invasion (EMVI) (P<0.001). The median follow-up time was 71 months. The 5-year OS was 84.1% and 96.5% (P<0.001), and the 5-year DFS was 75.6% and 91.3% (P<0.001) for PNI-positive (+) and PNI-negative (-) patients, respectively. The multivariate regression analyses identified PNI as an independent negative prognostic factor for DFS [hazard ratio (HR): 2.95; 95% confidence interval (CI), 1.546-5.626; P=0.001] and OS (HR: 3.966; 95% CI, 1.642-9.575; P=0.002). Among PNI (+) patients, DFS and OS were positively correlated with CEA levels (P=0.005 and P=0.004, respectively). Postoperative chemotherapy failed to improve DFS (P=0.480 and P=0.267, respectively) and OS (P=0.940 and P=0.077, respectively) regardless of whether the patients were PNI positive or not.
    Conclusions: In stage II CRC patients, PNI was a poor independent predictor for DFS and OS. Among PNI (+) patients, CEA levels were positively correlated with DFS and OS. Traditional postoperative adjuvant chemotherapy does not improve outcomes of PNI (+) patients. Therefore, as to the active role of PNI and vacancy for treatment in allusion to PNI, follow-up of PNI (+) patients with elevated CEA level should be strengthened and further research on drug conducted on PNI deserve to be carried on.
    Keywords:  Colorectal cancer (CRC); perineural invasion (PNI); postoperative adjuvant chemotherapy
    DOI:  https://doi.org/10.21037/jgo-22-277
  5. J Clin Med. 2022 Apr 23. pii: 2367. [Epub ahead of print]11(9):
    Perineural Invasion in Pancreatic Ductal Adenocarcinoma (PDAC): A Saboteur of Curative Intended Therapies?
    Matthäus Felsenstein, Flora Lindhammer, Mathilde Feist, Karl Herbert Hillebrandt, Lea Timmermann, Christian Benzing, Brigitta Globke, Dario Zocholl, Mengwen Hu, Uli Fehrenbach, Bruno Valentin Sinn, Uwe Pelzer, Igor Maximillian Sauer, Johann Pratschke, Thomas Malinka.
      (1) Background: Perineural invasion (PNI) is a common characteristic of pancreatic ductal adenocarcinoma (PDAC) and is present in most resection margins. We hypothesized that curative pancreatic tumor resection with long-term survival could only be achieved in PNI-negative patients. (2) Material and Methods: A retrospective investigation of PDAC patients who underwent curative-intended surgery during the period 2008 to 2019 was performed at our institution. (3) Results: We identified 571 of 660 (86.5%) resected patients with well-annotated reports and complete datasets. Of those, 531 patients (93%) exhibited tumors with perineural invasion (Pn1), while 40 (7%) were negative for PNI (Pn0). The majority of patients in the Pn1 group presented advanced tumor stage and positive lymph node infiltration. Patients in the Pn0 group showed an improved disease-free and long-term survival compared to the Pn1 group (p &lt; 0.001). Subgroup analysis of all R0-resected patients indicated improved long-term survival and disease-free survival of R0 Pn0 patients when compared to R0 Pn1 patients (p &lt; 0.001). (4) Conclusion: Our study confirmed that Pn0 improves the long-term survival of PDAC-resected cancer patients. Furthermore, PNI significantly challenges the long-term survival of formally curative (R0) resected patients. We provide new insights into the dynamics of PNI in pancreatic cancer patients which are needed to define subgroups of patients for risk stratification and multimodal treatment strategies.
    Keywords:  pancreatic ductal adenocarcinoma; perineural invasion; risk stratification
    DOI:  https://doi.org/10.3390/jcm11092367
  6. Cancers (Basel). 2022 Apr 30. pii: 2253. [Epub ahead of print]14(9):
    Chronic Cancer Pain: Opioids within Tumor Microenvironment Affect Neuroinflammation, Tumor and Pain Evolution.
    Angela Santoni, Matteo Santoni, Edoardo Arcuri.
      Pain can be a devastating experience for cancer patients, resulting in decreased quality of life. In the last two decades, immunological and pain research have demonstrated that pain persistence is primarily caused by neuroinflammation leading to central sensitization with brain neuroplastic alterations and changes in pain responsiveness (hyperalgesia, and pain behavior). Cancer pain is markedly affected by the tumor microenvironment (TME), a complex ecosystem consisting of different cell types (cancer cells, endothelial and stromal cells, leukocytes, fibroblasts and neurons) that release soluble mediators triggering neuroinflammation. The TME cellular components express opioid receptors (i.e., MOR) that upon engagement by endogenous or exogenous opioids such as morphine, initiate signaling events leading to neuroinflammation. MOR engagement does not only affect pain features and quality, but also influences directly and/or indirectly tumor growth and metastasis. The opioid effects on chronic cancer pain are also clinically characterized by altered opioid responsiveness (tolerance and hyperalgesia), a hallmark of the problematic long-term treatment of non-cancer pain. The significant progress made in understanding the immune-mediated development of chronic pain suggests its exploitation for novel alternative immunotherapeutic approaches.
    Keywords:  cancer pain; immunotherapy; neuroinflammation; opioid-induced hyperalgesia; tumor microenvironment
    DOI:  https://doi.org/10.3390/cancers14092253
  7. Adv Biol (Weinh). 2022 May 09. e2200020
    The µ-Opioid Receptor in Cancer and Its Role in Perineural Invasion: A Short Review and New Evidence.
    Juan P Cata, Megan L Uhelski, Aysegul Gorur, Siddhant Bhoir, Nisa Ilsin, Patrick M Dougherty.
      Cancer is a significant public health problem worldwide. While there has been a steady decrease in the cancer death rate over the last two decades, the number of survivors has increased and, thus, cancer-related sequela. Pain affects the life of patients with cancer and survivors. Prescription opioids continue as the analgesic of choice to treat moderate-to-severe cancer-related pain. There has been controversy on whether opioids impact cancer progression by acting on cancer cells or the tumor microenvironment. The μ-opioid receptor is the site of action of prescription opioids. This receptor can participate in an important mechanism of cancer spread, such as perineural invasion. In this review, current evidence on the role of the μ-opioid receptor in cancer growth is summarized and preliminary evidence about its effect on the cross-talk between sensory neurons and malignant cells is provided.
    Keywords:  cancer progression; opioids; perineural invasion; µ-opioid receptor
    DOI:  https://doi.org/10.1002/adbi.202200020
  8. FASEB J. 2022 May;36 Suppl 1
    Mapping and specific viral targeting of peripheral pancreatic innervation.
    Maria Jimenez Gonzalez, Rosemary Li, Lisa E Pomeranz, Alexandra Alvarsson, Roberta Marongiu, Rollie F Hampton, Rupangi C Vasavada, Gary J Schwartz, Sarah A Stanley.
      Neuronal inputs from central nervous system (CNS) are essential in regulating pancreatic endocrine function. It has been shown that perturbation of CNS activity alters pancreatic hormone release. CNS and peripheral organs constantly communicate through the peripheral nervous system (PNS), which can be divided into autonomic efferent (parasympathetic and sympathetic) and afferent sensory nervous systems. While we know that the pancreas is densely innervated by the PNS, we lack a comprehensive map of peripheral ganglia providing inputs to the pancreas. These data could provide crucial information about pancreatic function. Published studies suggest parasympathetic inputs to the pancreas lower blood glucose by enhancing insulin secretion. On the other hand, sympathetic action results in increased blood glucose levels by stimulating glucagon secretion and inhibiting insulin. However, these studies are based on electrical stimulation or transection of peripheral splachnic and vagal nerves that may affect the activity of other metabolically active organs (liver, stomach, intestine,). Highly targeted modulation of specific pancreatic nerve activity in health and pancreatic diseases requires new approaches. In the present project, we provide a detailed map of the distribution of peripheral pancreas-innervating neurons using retrograde tracing, tissue clearing and 3D imaging techniques (Idisco+). We show that a substantial pancreatic innervation (Fig 1b) with significant neuronal populations in sympathetic, parasympathetic and sensory ganglia projecting to pancreatic tissue (Fig 1 c,d). In addition, we achieved targeted gene delivery to specific pancreatic efferent and afferent pathways by optimizing adeno-associated viral serotypes (AAV), promoters, titers and delivery (Fig2 a-d). By utilizing our optimized approach, we show that highly targeted chemogenetic neural activation of intrapancreatic parasympathetic cholinergic neurons increased plasma insulin and significantly improved glucose tolerance in male mice (Fig 2 e,f). Additionally, using a dual viral strategy to specifically target pancreas-projecting sympathetic neurons, we demonstrated that targeted activation of pancreas-projecting sympathetic neurons impaired glucose tolerance in male mice (Fig 2g,h). Our innovative viral approaches allow highly targeted gene expression and neuromodulation of defined pancreatic nerves. These methodologies will allow examination of functional roles of pancreatic parasympathetic and sympathetic innervation in glucose metabolism as well as in digestion (exocrine function). Our work also allow for future studies to determine the specific contribution of pancreatic innervation to metabolic diseases, pancreatic inflammation and cancer.
    DOI:  https://doi.org/10.1096/fasebj.2022.36.S1.R2070
  9. FASEB J. 2022 May;36 Suppl 1
    SPARC: Visualization of genetically-labeled vagal and spinal afferent subsets innervating the mouse lung.
    Seol-Hee Kim, Mayur Patil, Parmvir Bahia, Stephen Hadley, Thomas Taylor-Clark.
      Pulmonary functions are controlled by afferent nerves which convey peripheral information to the central nervous system. Cell bodies of these afferent nerves are found predominantly in the vagal ganglia (VG) with some in the dorsal root ganglia (DRG). These neurons are highly heterogeneous based on their developmental origins, anatomical sources, and physiochemical properties. Vagal ganglia are composed of nodose (placode origin), and jugular ganglia (neural crest origin). Most vagal afferent nerves innervating the lung are unmyelinated C-fibers which are activated by capsaicin, the selective agonist of transient receptor potential vanilloid 1 (TRPV1). TRPV1 detects noxious stimuli and its activation results in defensive reflexes. Both nodose and jugular ganglia have TRPV1+ nociceptive C-fiber but it is not currently known where they terminate within the lung. In addition, there is lack of information regarding pulmonary afferent nerves projecting from the DRG, which also are derived from the neural crest. Here, we used cell-type specific Cre knock-in strains in combination with injections with adeno-associated viral vectors (AAV) carrying a Cre-sensitive reporter allele to label specific subsets of vagal and DRG afferent nerves in lung. Pirt-cre (marker for all sensory neurons), TRPV1-cre (nociceptors) and Tac1-cre (jugular, DRG) strains received unilateral injections of AAV9-flex-EGFP into nodose ganglia, and/or AAV9-flex-tdTomato into thoracic DRG (between T1-T3). VG, DRG and lung were collected 4 weeks post-injection and cryosectioned. Native fluorescent signals were amplified using anti-DsRed and anti-GFP immunoreactivity, and images were taken using an Andor Dragonfly spinning disk confocal microscope. Viral transfection was confirmed by expression of GFP in VG or tdTomato in DRG. Lung images were analyzed for VG/DRG nerve innervations based on diameters of airways (small: ≤175 µm, medium: 175-376 µm, large: ≥376 µm). >95% of the conducting airways was innervated by vagal Pirt+ afferent nerves. About half of the conducting airways also had vagal Pirt+ fibers which projected out into the alveolar regions (mean distance 200±50 µm). Only 20% of the airways were innervated by Pirt+ DRG fibers, none of which projected into the alveolar regions. Vagal-Pirt(+) nerves innervate most of the airways regardless of size, but DRG-Pirt(+) nerves innervate mostly large diameter airways. ~75% of airways are innervated by vagal TRPV1+ afferents, some of which project into the alveolar regions. There is virtually no TRPV1+ innervation of the lung projected from the DRG. ~75% of large/medium sized airways were innervated by vagal originating nerves in Tac1-cre, but none of these fibers projected into the alveolar spaces. Some large diameter airways were also innervated by Tac1+ fibers from DRG neurons. Together, our approach with the unilateral intraganglionic injections of AAV, into the VG and DRG, carrying a cre-dependent reporter allele allows identification of specific subsets of afferent nerves in the VG and DRG innervating the lung.
    DOI:  https://doi.org/10.1096/fasebj.2022.36.S1.R2052
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